CNS regulation of glucose metabolism. (a) Neuronal pathways including the melanocortin system potentiate insulin’s ability to inhibit hepatic glucose production and to increase glucose uptake into muscle and fat. Insulin and leptin, which circulate at levels proportionate to body adiposity, activate neuronal glucose-lowering pathways. Since the same neuroendocrine control system is critical for normal energy homeostasis (b), defects in its signaling can induce both insulin resistance and obesity via distinct but complementary mechanisms and thus predispose to type 2 diabetes.